DESCRIPTION: The ongoing HIV/AIDS pandemic has resulted in more than 60 million infections worldwide and left more than 30 million people dead. Despite more than 30 years of concerted efforts, no HIV vaccine candidate to date has demonstrated a meaningful capacity to prevent the nearly 2 million new infections each year. Drug abusers are at heightened peril for acquisition of HIV by virtue of the negative consequences of drug abuse on overall health and the high risk behaviors associated with addiction. Thus, there is a clear need for revolutionary approaches to the development of a preventative HIV vaccine to reduce the burden of AIDS in drug abuse. Although the exact correlates of effective immunity against HIV remain elusive, antibodies that can mediate broad neutralizing activity or antibody-dependent cell-mediated cytotoxicity (ADCC) are widely considered to be critical components of a successful preventative vaccine against HIV. However, broadly neutralizing antibodies (bnAbs) are relatively rare in the HIV-infected population, and usually appear very late in infection. Moreover, a detailed analysis of HIV-specific bnAbs reveals substantial mutation from the germ line immunoglobulin sequence, indicating that a sustained, determined germinal center response is likely required to facilitate sufficient affinity maturation of the HIV-specific antiboy response. An efficient germinal center response depends upon a specialized subset of follicular helper CD4 T cells (TFH), which support B cell proliferation and somatic hypermutation. Thus, an improved understanding of host and viral mechanisms that limit germinal center efficiency should enable design of more efficacious HIV vaccines. Natural killer (NK) cells are classically thought to primarily contribute to antiviral immunity through lysis of virus- infected cells. However, we recently demonstrated that NK cells play a vital regulatory role in the context of chronic lymphocytic choriomeningitis virus (LCMV) infection in mice. NK cell-mediated killing of activated CD4 T cells predisposed virus-specific CD8 T cell to become functionally exhausted, thereby favoring host survival and persistent virus infection rather than fatal immune pathology. More recently, we found that NK cells also restrict the germinal center response after acute LCMV infection and significantly contribute to the delayed and weak induction of virus-specific neutralizing antibodies. Taken together, our findings support the organizing hypothesis that inventive strategies to circumvent this immunoregulatory activity of NK cells represent a radically innovative approach to the development of an efficacious HIV vaccine. The goal of this application is to gain a clear mechanistic understanding of the contribution of a novel NK cell immunoregulatory function to controlling development of protective immunity after vaccination. In the long-term, the findings obtained in this proposal should be transformative with regards to the design of a next-generation vaccine to control the HIV/AIDS epidemic.